Research ArticleHIV

3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope–specific plasma cells and humoral immunity in nonhuman primates

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Science Immunology  19 Jun 2020:
Vol. 5, Issue 48, eabb1025
DOI: 10.1126/sciimmunol.abb1025

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Live long and protect

While vaccines elicit robust short-term responses, maintaining sustained and durable antibody responses to vaccines remains a challenge. Durability of antibody responses not only depends on the antigen but also on the adjuvants used in the vaccine. Here, Kasturi et al. have used a nanoparticle and a clinically applicable alum adsorbed formulation of 3M-052, a TLR7/8 agonist to promote sustained antibody responses to an HIV-1 envelope (Env) protein vaccine in rhesus macaques. They report that 3M-052–adjuvanted Env vaccination led to the development of durable antibody responses that were readily detectable a year after immunization, and they attribute this to the ability of 3M-052 to prime and sustain long-lived plasma cell responses. 3M-052 now joins an elite set of adjuvants that could help shape vaccination in the 21st century.

Abstract

A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C–derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)–7/8 agonist named 3M-052 formulated in poly(lactic-co-glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (TFH) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs.

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